Powder Delivery Devices

ABSTRACT

A nasal delivery device for delivering substance to a nasal cavity of a subject, the delivery device comprising: a substance supply unit for supplying a dose of substance to be delivered to the nasal cavity of the subject, the substance supply unit including an inlet and an outlet; a nosepiece unit including a nosepiece for fitting to a nasal cavity of the subject and being in fluid communication with the outlet of the substance supply unit; and a mouthpiece unit including a mouthpiece in fluid communication with the inlet of the substance supply unit and through which the subject in use exhales such as to entrain substance from the container chamber and deliver the same through the nosepiece, and at least one temperature modifier for reducing a temperature of the exhaled air flow such as to reduce the absolute humidity thereof.

CROSS REFERENCE TO PRIOR APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/816,984, filed on Jun. 10, 2009, now U.S. patent Ser. No. ______,which in turn is a U.S. national stage entry of PCT/GB06/00631, filedFeb. 23, 2006, which claims priority to GB0503738.7, filed Feb. 23,2005. The content of all the prior applications is hereby incorporatedby reference in its entirety.

FIELD OF INVENTION

The present invention relates to a powder delivery device for thedelivery of a powdered substance, in particular to the nasal airway, andboth a powdered substance and a capsule for use with the same.

BACKGROUND

There is an increasing interest in the nasal delivery of substances,typically pharmaceutical drugs, both as powders and liquids, for topicaland systemic delivery.

Current delivery systems are not suited to the delivery of substances tothe upper posterior region of the nasal airway, in particular targeteddelivery to the olfactory region and the sinus ostia.

U.S. Pat. No. 4,013,075 and U.S. Pat. No. 4,889,114 disclose examples ofprior art inhalation devices, which provide for the inhalation of apowdered substance from a capsule.

WO-A-00/051672, the content of which is herein incorporated byreference, discloses a delivery device for delivering a substance, inparticular a medicament, in a bi-directional flow through the nasalcavities, that is, an air flow which passes into one nostril, around theposterior margin of the nasal septum and in the opposite direction outof the other nostril. A particular feature of this bi-directional modeof delivery is the ability to target defined regions in the nasalairway, for both topical and systemic delivery, in particular the upperposterior region which cannot be targeted with existing systems.

SUMMARY OF THE INVENTION

The present inventors have recognized that the delivery of powderedsubstances using the exhalation breath of a subject still presents asignificant challenge, owing to the interaction of the moist exhaled airflow with the powdered substance prior to delivery into the nasalairway.

Exhalation into a device leads to condensation on the surfaces of theexposed device components, where the components are at a significantlylower temperature than the exhaled air flow, and significantcondensation in the delivery channel will affect the consistency of thedelivered doses.

It is an aim of the present invention to provide a delivery device whichallows for the delivery of powdered substances, either supplied incapsules or blisters, which contain a pre-metered dose of substance withthe appropriate particle size distribution and surface properties, ormetered from bulk, where using the exhalation breath of the subject.

In one aspect the present invention provides a nasal delivery devicewhich utilizes an exhalation breath to deliver a powdered substance, andincludes a temperature modifier to reduce the absolute humidity of theexhaled air flow prior to entrainment of the powdered substance.

In another aspect the present invention provides a nasal delivery devicewhich utilizes an exhalation breath to deliver a powdered substance, andincorporates a Venturi unit to draw a powdered substance into theexhaled air flow using an air flow of the ambient atmosphere.

In a further aspect the present invention provides a nasal deliverydevice which utilizes drive means, such as a pressurized gas supply or aturbine, to entrain a powdered substance into a substance gas flow,which in one embodiment is then entrained by an exhaled air flow.

In a yet further aspect the present invention provides a capsule whichis formed from a lightweight material, such as a thin-wall sectionpolymeric material, which reduces the energy required to move thecapsule, typically by one or both of vibration and rotation, and therebyprovides for emptying at reduced flow rates. In one embodiment thematerial has a reduced tendency to become tacky in the presence ofmoisture.

In a still further aspect the present invention provides a powderformulation which is formulated to have reduced hygroscopicity, andpreferably a transiently-increased dissolution time, such as achieved bycoating or blending, such as to reduce any loss of powdered substance ina device due to interaction with water condensate.

In one preferred aspect the present invention provides a nasal deliverydevice for delivering substance to a nasal cavity of a subject, thedelivery device comprising: a substance supply unit for supplying a doseof substance to be delivered to the nasal cavity of the subject, thesubstance supply unit including an inlet and an outlet; a nosepiece unitincluding a nosepiece for fitting to a nasal cavity of the subject andbeing in fluid communication with the outlet of the substance supplyunit; and a mouthpiece unit including a mouthpiece in fluidcommunication with the inlet of the substance supply unit and throughwhich the subject in use exhales such as to entrain substance from thesubstance supply unit and deliver the same through the nosepiece, and atleast one temperature modifier for reducing a temperature of the exhaledair flow such as to reduce the absolute humidity thereof.

In one embodiment the at least one temperature modifier comprises atleast one elongate channel.

Preferably, the at least one temperature modifier comprises a pluralityof elongate channels.

In one embodiment the mouthpiece unit includes a plurality oftemperature modifiers which can be fluidly connected successively to themouthpiece, and a switching mechanism which allows for one of thetemperature modifiers to be fluidly connected to the mouthpiece.

Preferably, when the one of the temperature modifiers is fluidlyconnected to the mouthpiece, the at least one other temperature modifieris vented to atmosphere.

In one embodiment the switching mechanism comprises a rotatable memberto which the temperature modifiers are disposed, whereby rotation of theswitching mechanism provides for the one of the temperature modifiers tobe in fluid communication with the mouthpiece.

Preferably, the substance supply unit comprises a container chamber forreceiving a substance-containing container which contains a dose ofsubstance.

In one embodiment the container chamber is substantially cylindrical inshape.

In another embodiment the container chamber is substantially sphericalin shape.

In one embodiment the container chamber and the nosepiece comprise aunitary, replaceable component.

In one embodiment the substance supply unit comprises a rupturingmechanism for rupturing the container as contained in the containerchamber.

In one embodiment the container is formed of a material which exhibitsinsufficient tackiness, and preferably substantially no surfacetackiness, in the presence of moisture such as not to adhere to an innersurface of the container chamber during emptying of the container.

Preferably, the container is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 5 s following exhalation.

More preferably, the container is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s following exhalation.

Still more preferably, the container is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s followingexhalation.

In one embodiment the container is formed substantially of a cellulosederivative.

Preferably, the container is formed substantially of one ofhydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose and carboxymethylcellulose.

In another embodiment the container is formed substantially of gelatine.

In a further embodiment the container is formed of a plastics material.

In a still further embodiment the container includes a coating of amaterial which exhibits insufficient tackiness in the presence ofmoisture such as not to adhere to an inner surface of the containerchamber during emptying of the container.

Preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 5 s following exhalation.

More preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s following exhalation.

Still more preferably, the coating is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s followingexhalation.

Preferably, the coating comprises substantially one of parylene,hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylalcohol, acrylic acid polymer, methacrylic acid polymer, ethyl acrylicacid polymer, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxyl methylcelluloseacetate succinate, or any combination of layers thereof.

In one embodiment the container comprises a body of gelatine.

In one embodiment the container comprises a capsule.

In one embodiment the capsule is substantially cylindrical in shape.

In another embodiment the capsule is substantially spherical in shape.

In one embodiment the at least one temperature modifier is configured toreduce the temperature of the exhaled air flow by more than about 5° C.

Preferably, the at least one temperature modifier is configured toreduce the temperature of the exhaled air flow by at least about 12° C.

Preferably, the at least one temperature modifier is configured to allowa flow therethrough at a flow rate of at least about 10 l/min at apressure of less than about 2 kPa, and preferably less than about 1 kPa.

More preferably, the at least one temperature modifier is configured toallow a flow therethrough at a flow rate of at least about 20 l/min at apressure of less than about 2 kPa, and preferably less than about 1 kPa.

Still more preferably, the at least one temperature modifier isconfigured to allow a flow therethrough at a flow rate of at least about30 l/min at a pressure of less than about 2 kPa, and preferably lessthan about 1 kPa.

Yet more preferably, the at least one temperature modifier is configuredto allow a flow therethrough at a flow rate of at least about 40 l/minat a pressure of less than about 2 kPa, and preferably less than about 1kPa.

Still yet more preferably, the at least one temperature modifier isconfigured to allow a flow therethrough at a flow rate of at least about50 l/min at a pressure of less than about 2 kPa, and preferably lessthan about 1 kPa.

Preferably, the at least one temperature modifier is configured such asto provide a pressure drop of not more than about 0.5 kPa to the exhaledair flow.

More preferably, the at least one temperature modifier is configuredsuch as to provide a pressure drop of not more than about 0.25 kPa tothe exhaled air flow.

Still more preferably, the at least one temperature modifier isconfigured such as to provide a pressure drop of not more than about0.10 kPa to the exhaled air flow.

Yet more preferably, the at least one temperature modifier is configuredsuch as to provide a pressure drop of not more than about 0.05 kPa tothe exhaled air flow.

Still yet more preferably, the at least one temperature modifier isconfigured such as to provide a pressure drop of not more than about0.025 kPa to the exhaled air flow.

In another embodiment the at least one temperature modifier comprises athermoelectric device.

In another preferred aspect the present invention provides a nasaldelivery device for delivering substance to a nasal cavity of a subject,the delivery device comprising: a substance supply unit for supplying adose of substance to be delivered to the nasal cavity of the subject,the substance supply unit comprising a substance-receiving chamberincluding an inlet and an outlet, and a Venturi unit for drawing a flowof ambient air through the substance-receiving chamber; a nosepiece unitincluding a nosepiece for fitting to the nasal cavity of the subject andbeing in fluid communication with the Venturi unit; and a mouthpieceunit including a mouthpiece in fluid communication with the Venturi unitand through which the subject in use exhales such as to entrainsubstance from the substance-receiving chamber and deliver the samethrough the nosepiece.

Preferably, the substance-receiving chamber comprises a containerchamber for receiving a substance-containing container which contains adose of substance.

In one embodiment the container chamber is substantially cylindrical inshape.

In another embodiment the container chamber is substantially sphericalin shape.

In one embodiment the container chamber and the nosepiece comprise aunitary, replaceable component.

In one embodiment the substance supply unit comprises a rupturingmechanism for rupturing the substance-containing container as containedin the container chamber.

In one embodiment the container is formed of a material which exhibitsinsufficient tackiness, and preferably substantially no surfacetackiness, in the presence of moisture such as not to adhere to an innersurface of the container chamber during emptying of the container.

Preferably, the container is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 5 s following exhalation.

More preferably, the container is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s following exhalation.

Still more preferably, the container is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s followingexhalation.

In one embodiment the container is formed substantially of a cellulosederivative.

Preferably, the container is formed substantially of one ofhydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose and carboxymethylcellulose.

In another embodiment the container is formed substantially of gelatine.

In a further embodiment the container is formed of a plastics material.

In a still further embodiment the container includes a coating of amaterial which exhibits insufficient tackiness in the presence ofmoisture such as not to adhere to an inner surface of the containerchamber during emptying of the container.

Preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 5 s following exhalation.

More preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s following exhalation.

Still more preferably, the coating is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s followingexhalation.

Preferably, the coating comprises substantially one of parylene,hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylalcohol, acrylic acid polymer, methacrylic acid polymer, ethyl acrylicacid polymer, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxyl methylcelluloseacetate succinate, or any combination of layers thereof.

In one embodiment the container comprises a body of gelatine.

In one embodiment the container comprises a capsule.

In one embodiment the capsule is substantially cylindrical in shape.

In another embodiment the capsule is substantially spherical in shape.

In one embodiment the Venturi unit comprises a first, driving air flowinlet which is in fluid communication with the mouthpiece unit andprovides a constriction which acts to accelerate the exhaled air flow todeliver a driving air flow at a higher velocity, a second, substance airflow inlet which is in fluid communication with the substance supplyunit and through which is in use drawn a substance air flow from thesubstance-receiving chamber which entrains substance as containedtherein, and an air flow outlet which is in fluid communication with thenosepiece unit and through which the driving air flow and the substanceair flow are in use delivered.

In one embodiment the driving air flow is directed substantiallyperpendicularly to the substance air flow.

In another embodiment the driving air flow is directed substantiallyparallel to the substance air flow.

In one embodiment the mouthpiece unit is fluidly connected to thesubstance supply unit, such as to provide a supplemental air flow to thesubstance-receiving chamber on exhalation by the subject into themouthpiece unit.

Preferably, the mouthpiece unit includes a flow channel which is fluidlyconnected to the inlet of the substance-receiving chamber.

In a further preferred aspect the present invention provides a nasaldelivery device for delivering substance to a nasal cavity of a subject,the delivery device comprising: a substance supply unit for supplying adose of substance to be delivered to the nasal cavity of the subject,the substance supply unit comprising a substance-receiving chamberincluding an inlet and an outlet, and a gas supply unit for delivering agas flow through the substance-receiving chamber such as in use toprovide a gas flow entraining substance from the outlet of thesubstance-receiving chamber; a nosepiece unit including a nosepiece forfitting to the nasal cavity of the subject and being in fluidcommunication with the outlet of the substance-receiving chamber; and amouthpiece unit including a mouthpiece in fluid communication with theoutlet of the substance-receiving chamber and the nosepiece and throughwhich the subject in use exhales such as to entrain substance asdelivered from the substance-receiving chamber and deliver the samethrough the nosepiece.

Preferably, the substance-receiving chamber comprises a containerchamber for receiving a substance-containing container which contains adose of substance.

In one embodiment the container chamber is substantially cylindrical inshape.

In another embodiment the container chamber is substantially sphericalin shape.

In one embodiment the container chamber and the nosepiece comprise aunitary, replaceable component.

In one embodiment the substance supply unit comprises a rupturingmechanism for rupturing the container as contained in the containerchamber.

In one embodiment the container is formed of a material which exhibitsinsufficient tackiness, and preferably substantially no surfacetackiness, in the presence of moisture such as not to adhere to an innersurface of the container chamber during emptying of the container.

Preferably, the container is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 5 s following exhalation.

More preferably, the container is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s following exhalation.

Still more preferably, the container is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s followingexhalation.

In one embodiment the container is formed substantially of a cellulosederivative.

Preferably, the container is formed substantially of one ofhydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose and carboxymethylcellulose.

In another embodiment the container is formed substantially of gelatine.

In a further embodiment the container is formed of a plastics material.

In a still further embodiment the container includes a coating of amaterial which exhibits insufficient tackiness in the presence ofmoisture such as not to adhere to an inner surface of the containerchamber during emptying of the container.

Preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 5 s following exhalation.

More preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s following exhalation.

Still more preferably, the coating is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s followingexhalation.

Preferably, the coating comprises substantially one of parylene,hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylalcohol, acrylic acid polymer, methacrylic acid polymer, ethyl acrylicacid polymer, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxyl methylcelluloseacetate succinate, or any combination of layers thereof.

In one embodiment the container comprises a body formed substantially ofgelatine.

In one embodiment the container comprises a capsule.

In one embodiment the capsule is substantially cylindrical in shape.

In another embodiment the capsule is substantially spherical in shape.

In one embodiment the gas supply unit comprises a volume of pressurizedgas which, when released, provides the entraining gas flow.

In another embodiment the gas supply unit comprises a charged turbinewhich, when released, provides the entraining gas flow.

In one embodiment the gas supply unit is a breath-actuated unit.

In one embodiment the gas supply unit is actuated in response togeneration of a predeterminable flow rate through the mouthpiece unit.

In another embodiment the gas supply unit is actuated in response togeneration of a predeterminable pressure at the mouthpiece unit.

In another embodiment the gas supply unit is a manually-actuated unit.

In a still further preferred aspect the present invention provides acapsule for containing a powdered substance which exhibits insufficienttackiness, and preferably no surface tackiness, in the presence ofmoisture such as not to adhere to an inner surface of a capsule chamberwhich contains the capsule during emptying of the capsule.

Preferably, the capsule is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in an exhalation airflow for a period of up to about 5 s.

More preferably, the capsule is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s.

Still more preferably, the capsule is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s.

In one embodiment the capsule is formed substantially of a cellulosederivative.

Preferably, the capsule is formed substantially of one of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, methylcellulose,ethylcellulose and carboxymethylcellulose.

In another embodiment the capsule is formed of a plastics material.

In one embodiment the capsule includes a coating of a material whichexhibits insufficient tackiness in the presence of moisture such as notto adhere to an inner surface of the capsule chamber during emptying ofthe capsule.

Preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in an exhalation airflow for a period of up to about 5 s.

More preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s.

Still more preferably, the coating is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s.

Preferably, the coating comprises substantially one of parylene,hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylalcohol, acrylic acid polymer, methacrylic acid polymer, ethyl acrylicacid polymer, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxyl methylcelluloseacetate succinate, or any combination of layers thereof.

In one embodiment the capsule comprises a body formed substantially ofgelatine.

In one embodiment the capsule is substantially cylindrical in shape.

In another embodiment the capsule is substantially spherical in shape.

In one embodiment the capsule comprises a body of thin-wall section.

Preferably, the body has a thickness of not more than about 0.25 mm.

More preferably, the body has a thickness of not more than about 0.20mm.

In a yet further preferred aspect the present invention extends to theuse of a capsule, containing a powdered substance, which exhibitsinsufficient tackiness, and preferably no surface tackiness, in thepresence of moisture such as not to adhere to an inner surface of acapsule chamber which contains the same during emptying of the capsulein an exhaled air flow.

Preferably, the capsule is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in an exhalation airflow for a period of up to about 5 s.

More preferably, the capsule is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s.

Still more preferably, the capsule is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s.

In one embodiment the capsule is formed substantially of a cellulosederivative.

Preferably, the capsule is formed substantially of one of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, methylcellulose,ethylcellulose and carboxymethylcellulose.

In another embodiment the capsule is formed of a plastics material.

In one embodiment the capsule includes a coating of a material whichexhibits insufficient tackiness in the presence of moisture such as notto adhere to an inner surface of the capsule chamber during emptying ofthe capsule.

Preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in an exhalation airflow for a period of up to about 5 s.

More preferably, the coating is formed of a material which exhibitsinsufficient tackiness in the presence of moisture in the exhalation airflow for a period of up to about 2 s.

Still more preferably, the coating is formed of a material whichexhibits insufficient tackiness in the presence of moisture in theexhalation air flow for a period of up to about 1 s.

Preferably, the coating comprises substantially one of parylene,hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylalcohol, acrylic acid polymer, methacrylic acid polymer, ethyl acrylicacid polymer, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxyl methylcelluloseacetate succinate, or any combination of layers thereof.

In one embodiment the capsule comprises a body formed substantially ofgelatine.

In one embodiment the capsule is substantially cylindrical in shape.

In another embodiment the capsule is substantially spherical in shape.

In one embodiment the capsule comprises a body of thin-wall section.

Preferably, the body has a thickness of not more than about 0.25 mm.

More preferably, the body has a thickness of not more than about 0.20mm.

In yet another preferred aspect the present invention provides a nasaldelivery device for delivering substance to a nasal cavity of a subject,the delivery device comprising: a substance supply unit for supplying adose of substance to be delivered to the nasal cavity of the subject,the substance supply unit including an inlet and an outlet; a nosepieceunit including a nosepiece for fitting to a nasal cavity of the subjectand being in fluid communication with the outlet of the substance supplyunit; and a mouthpiece unit including a mouthpiece in fluidcommunication with the inlet of the substance supply unit and throughwhich the subject in use exhales such as to entrain substance from thesubstance supply unit and deliver the same through the nosepiece.

In still another preferred aspect the present invention provides amethod of delivering substance to a nasal cavity of a subject, themethod comprising the steps of: supplying a dose of substance to bedelivered to the nasal cavity of the subject; fitting a nosepiece unitincluding a nosepiece to the nasal cavity of the subject; and thesubject exhaling through a mouthpiece unit such as to entrain thesupplied dose of substance and deliver the same through the nosepiece tothe nasal cavity of the subject, wherein the mouthpiece unit includes atleast one temperature modifier for reducing a temperature of the exhaledair flow such as to reduce the absolute humidity thereof.

In yet still another preferred aspect the present invention provides amethod of delivering substance to a nasal cavity of a subject, themethod comprising the steps of: providing a dose of substance to bedelivered to the nasal cavity of the subject in a substance-receivingchamber; fitting a nosepiece unit including a nosepiece to the nasalcavity of the subject; providing a Venturi unit which is operative todraw a flow of ambient air through the substance-receiving chamber; andthe subject delivering an exhaled air flow to the Venturi unit such asto draw a flow of ambient air through the substance-receiving chamber,which entrains the powdered substance therein, and to the nosepiece suchas to deliver the exhaled air flow entraining the powdered substance tothe nasal cavity of the subject.

In a yet still further preferred aspect the present invention provides amethod of delivering substance to a nasal cavity of a subject, themethod comprising the steps of: providing a dose of substance to bedelivered to the nasal cavity of the subject in a substance-receivingchamber; fitting a nosepiece unit including a nosepiece to the nasalcavity of the subject; providing a gas flow of ambient air through thesubstance-receiving chamber, which entrains the powdered substancetherein; and the subject delivering an exhaled air flow to the nosepiecewhich entrains the gas flow entraining the powdered substance, such asto deliver the powdered substance to the nasal cavity of the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the present invention will now be describedhereinbelow by way of example only with reference to the accompanyingdrawings, in which:

FIG. 1 illustrates a delivery device in accordance with a firstembodiment of the present invention;

FIG. 2 illustrates the heat exchanger of the delivery device of FIG. 1;

FIG. 3 illustrates the delivery device of FIG. 1, in the operativestate;

FIG. 4 illustrates the mouthpiece unit of a delivery device as amodification of the delivery device of FIG. 1, in a first operativeconfiguration;

FIG. 5 illustrates the mouthpiece unit of FIG. 4, in a second operativeconfiguration;

FIG. 6 illustrates a delivery device in accordance with a secondembodiment of the present invention;

FIG. 7 illustrates the delivery device of FIG. 6, in the operativestate;

FIG. 8 illustrates a delivery device as a modification of the deliverydevice of FIG. 6;

FIG. 9 illustrates the delivery device of FIG. 8, in the operativestate;

FIG. 10 illustrates a delivery device in accordance with a thirdembodiment of the present invention;

FIG. 11 illustrates the delivery device of FIG. 10, in the operativestate;

FIG. 12 illustrates a delivery device in accordance with a fourthembodiment of the present invention;

FIG. 13 illustrates the delivery device of FIG. 12, in a first operativestate;

FIG. 14 illustrates the delivery device of FIG. 12, in a secondoperative state;

FIG. 15 illustrates a delivery device as one modification of thedelivery device of FIG. 12;

FIG. 16 illustrates a delivery device as one modification of thedelivery device of FIG. 1; and

FIG. 17 illustrates a delivery device as another modification of thedelivery device of FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

FIGS. 1 to 3 illustrate a delivery device in accordance with a firstembodiment of the present invention.

The delivery device comprises a substance supply unit 3 which includes achamber 5 which receives a capsule 7, which contains a metered amount ofa powdered substance which is to be delivered by the delivery device, arupturing mechanism 9 for rupturing the capsule 7, a mouthpiece unit 11which is in fluid communication with the chamber 5 and is gripped in usein the mouth of a subject, and a nosepiece unit 15 which is in fluidcommunication with the chamber 5 and is fitted to one nostril of thesubject. For ease of illustration, the delivery device is illustrated inan elongate configuration, but, in its practical embodiment, themouthpiece unit 11 and the nosepiece unit 15 are configured for fittingto the mouth and one nostril of the subject.

The substance supply unit 3 includes an inlet 17 which fluidly connectsthe chamber 5 thereof with the mouthpiece unit 11 and an outlet 19 whichfluidly connects the chamber 5 thereof with the nosepiece unit 15.

In this embodiment the substance supply unit 3 includes a grid 21, herea gauze, which is disposed at the outlet 19 thereof and acts to preventthe capsule 7 or parts thereof from escaping from the chamber 5.

In this embodiment the chamber 5 is cylindrical in shape.

In another embodiment the chamber 5 can be substantially spherical inshape, which is particularly advantageous in allowing for the release ofthe powdered substance from the capsule 7 in any operative position.

In this embodiment the chamber 5 and the grid 21, as components whichcontact the capsule 7 and the contained powder, are fabricated from amaterial having a low moisture sensitivity, here a plastics material,such as to reduce any tendency to become tacky in the presence ofmoisture, and therefore reduce the tendency for the capsule 7 and thepowdered substance as contained thereby to adhere to the wall of thechamber 5 or the grid 21.

In this embodiment the rupturing mechanism 9 comprises a piercingelement 23, here including two pins, which is operable to pierce thecapsule 7, and thereby provide for the release of the contained powderedsubstance on the generation of a flow through the chamber 5.

The mouthpiece unit 11 comprises a mouthpiece 25, in this embodiment asdefined by a tubular section, which is gripped in the mouth of thesubject, and a heat exchanger 27 which is in fluid communication withthe mouthpiece 25 and acts to draw heat from the exhaled air flow asdelivered through the mouthpiece 25, thus decreasing the temperature ofthe air flow as delivered to the chamber 5. By decreasing thetemperature of the air flow, the humidity of the air flow is reduced,with the water vapor condensing in the heat exchanger 27, and the impactof condensation is significantly reduced, thus allowing for successivedoses of powdered substance to be delivered without affecting therelease of powdered substance from the capsules 7.

As illustrated in FIG. 2, in this embodiment the heat exchanger 27comprises a channel 29 which has a zig-zag, serpentine configuration,with a circular cross section. In other embodiments the channel 29 couldhave other configurations, for example, a rectangular cross section.

In this embodiment the channel 29 has an effective length of 200 mm andan effective diameter of 4 mm, which reduces the temperature of anexhaled air flow which has a flow rate of 30 l/min to about 25° C. fromabout 37° C., where the channel 29 is at a temperature of 20° C.

The reduction in temperature is calculated as follows:

T _(e) =T _(w)−(T _(w) −T _(i))e ^(−hAmC)

Where: T_(e) is the fluid temperature at the exit of the channel 29;T_(w) is the fluid temperature at the wall of the channel 29; T_(i) isthe fluid temperature at the inlet of the channel 29; h is the heattransfer coefficient between the gas flowing through the channel 29 andthe material of the channel 29; A is the surface area of the channel 29;m is the mass flow rate; and is the specific heat capacity of the gasflowing through the channel 29. This calculation assumes turbulent flowin the channel 29 (Nu=0.023Re^(0.8)Pr^(0.3)).

In other embodiments the channel 29 can include features to enhance theheat transfer coefficient from the exhaled air flow to the wall of thechannel 29, such that the effective length of the channel 29 can beconsiderably reduced. Typical features include nodules or areas ofrelative surface roughness that create turbulence and so enhance theheat transfer.

In other embodiments the heat exchanger 27 could comprise a plurality ofchannels 29.

In one embodiment the heat exchanger 27 comprises four channels 29, asparallel ducts, which each have a width of 10 mm, a height of 1.5 mm anda length of 60 mm. This configuration reduces the temperature of anexhaled air flow which has a flow rate of 30 l/min by about 5° C., wherethe channels 29 are at a temperature of 20° C., and also cause only avery small pressure drop of 0.024 kPa.

The nosepiece unit 15 comprises a nosepiece 30, in this embodiment asdefined by a tubular section, which is inserted into a nostril of thesubject, in this embodiment to provide a sealing fit therewith.

In this embodiment the nosepiece 30, as a component which contacts thepowdered substance, is fabricated from a material having a low moisturesensitivity, here a plastics material, such as to reduce any tendency tobecome tacky in the presence of moisture, and therefore reduce thetendency for the powdered substance to adhere to the wall of thenosepiece 30.

In one embodiment the capsule 7 is a gelatine capsule.

In another embodiment the capsule 7 can be manufactured from a materialwhich has a reduced tendency to become tacky in the presence ofmoisture, as occurs with gelatine capsules, and therefore reduce thetendency for the capsule 7 to adhere to the wall of the chamber 5 or thegrid 21.

In one embodiment the capsule 7 is formed of a cellulose derivative,such as hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose and carboxymethylcellulose.

In another embodiment the capsule 7 can comprise a plastics material,preferably a water insoluble material, such as a polycarbonate.

In one embodiment the capsule 7 can be manufactured from a lightweightmaterial, such as thin-wall section polymeric materials, which reducesthe energy required to move the capsule 7, typically by one or both ofvibration and rotation, and thereby allow the delivery device to beoperated at reduced flow rates, which is particularly advantageous fornasal delivery.

In one embodiment the capsule 7 has a wall section of less than about0.25 mm, and more preferably less than about 0.2 mm.

In an alternative embodiment the capsule 7 can include an outer coatingof a material which has a reduced tendency to become tacky in thepresence of moisture, as occurs with gelatine capsules, and thereforereduce the tendency for the capsule 7 to adhere to the wall of thechamber 5 or the grid 21.

In one embodiment the coated capsule 7 can be formed of gelatine.

In one embodiment the coating can comprise one of parylene,hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylalcohol, acrylic acid polymer, methacrylic acid polymer, ethyl acrylicacid polymer, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxyl methylcelluloseacetate succinate.

The delivery device of this embodiment is operative to discharge thepowdered substance from the capsule 7 by rotation and vibration of thecapsule 7, and thus the capsule 7 is preferably formed of a material orcoated with a material which exhibits substantially no tackiness in thepresence of a moist environment, here a saturated exhaled air flow, thatis, does not exhibit an increased moisture content at the outer surfacethereof, which would prevent reliable rotation and vibration of thecapsule 7.

In this embodiment, as illustrated in FIG. 1, the capsule 7 iscylindrical in shape with hemispherical ends.

In other embodiments the capsule 7 could have other geometric forms,such as spherical, which allows for efficient powder release at low flowrates.

In one embodiment the capsule 7 can comprise two or more parts.

In one alternative embodiment the capsule 7 can be constructed to act asthe primary environmental barrier for the powdered substance. Forexample, the capsule 7 could be constructed from a relativelythick-walled cylindrical section of a polymeric material which includestwo metalized thin film closure members which act to seal the ends ofthe cylindrical section and thus enclose the same.

In one embodiment, where the delivery device is a re-usable device, thechamber 5, which contains the capsule 7, and the nosepiece 30 comprise aunitary, replaceable component.

In operation, as illustrated in FIG. 3, a subject operates the rupturingmechanism 9 to rupture the capsule 7, inserts the nosepiece 30 into oneof his/her nostrils, grips the mouthpiece 25 in his/her mouth, andexhales through the mouthpiece 25.

The exhaled air flow is reduced in temperature by the heat exchanger 27on delivery therethrough, such as to reduce the absolute humidity of theexhaled air flow, and this cooled air is then driven through the chamber5, which acts to move the capsule 7, in this embodiment by vibration androtation, and entrain the powdered substance as contained by the capsule7.

The exhaled air flow, as then entraining the powdered substance, isdelivered though the nosepiece 30 into one nasal cavity of the subject.

In this embodiment the exhaled air flow has such a pressure as to passaround the posterior region of the nasal septum, and into the othernasal cavity, thereby achieving a bi-directional air flow as describedin the applicants' earlier WO-A-00/051672.

In one modification, as illustrated in FIGS. 4 and 5, the mouthpieceunit 11 includes a plurality of, in this embodiment first and secondheat exchangers 27 a, b which can be used successively, such as to allowfor the evaporation of the condensed moisture from the one or morepreviously-used heat exchangers 27 a, b, and a switching mechanism 31which allows for one of the heat exchangers 27 a, b to be fluidlyconnected to the mouthpiece 25.

In this embodiment the switching mechanism 31 comprises a rotatablemember to which the heat exchangers 27 a, b are disposed, wherebyrotation of the switching mechanism 31 provides for one of the heatexchangers 27 a, b to be in fluid communication with the mouthpiece 25and the at least one other of the heat exchangers 27 a, b to be in fluidcommunication with the atmosphere. FIG. 4 illustrates a firstconfiguration, in which the first heat exchanger 27 a is in fluidcommunication with the mouthpiece 25 and the second heat exchanger 27 bis vented to atmosphere. FIG. 5 illustrates a second configuration, inwhich the second heat exchanger 27 b is in fluid communication with themouthpiece 25 and the first heat exchanger 27 a is vented to atmosphere.

With this configuration, the one of the heat exchangers 27 a, b which isin fluid communication with the mouthpiece 25 acts to cool the exhaledair flow as delivered therethrough, and thereby trap water vapor fromthe exhaled air, and the other of the heat exchangers 27 a, b which isvented to atmosphere provides for evaporation of the water condensate astrapped from a previous exhalation therethrough.

In an alternative embodiment the switching mechanism 31 could beoperatively coupled to the rupturing mechanism 9, such as to provide foroperation of the switching mechanism 31 with each operation of therupturing mechanism 9.

FIGS. 6 and 7 illustrate a nasal delivery device in accordance with asecond embodiment of the present invention.

The delivery device comprises a substance supply unit 103 which includesa chamber 105 which receives a capsule 107, which contains a meteredamount of a powdered substance which is to be delivered by the deliverydevice, a rupturing mechanism 109 for rupturing the capsule 107, aVenturi unit 110 which is in fluid communication with the chamber 105and is operative to draw an air flow of the ambient atmosphere throughthe chamber 105, a mouthpiece unit 111 which is in fluid communicationwith the Venturi unit 110 and is gripped in use in the mouth of asubject, and a nosepiece unit 114 which is in fluid communication withthe Venturi unit 110 and is fitted to one nostril of the subject. Forease of illustration, the delivery device is illustrated in an elongateconfiguration, but, in its practical embodiment, the mouthpiece unit 111and the nosepiece unit 114 are configured for fitting to the mouth andone nostril of the subject.

The substance supply unit 103 includes an inlet 117 which fluidlyconnects the chamber 105 thereof with the ambient atmosphere and anoutlet 119 which fluidly connects the chamber 105 thereof with theVenturi unit 110.

In this embodiment the substance supply unit 103 includes a grid 121,here a gauze, which is disposed at the outlet 119 thereof and acts toprevent the capsule 107 or parts thereof from escaping from the chamber105.

In this embodiment the chamber 105 is cylindrical in shape.

In another embodiment the chamber 105 could be spherical in shape, whichis particularly advantageous in allowing for the release of the powderedsubstance from the capsule 107 when in any operative position.

In this embodiment the chamber 105 and the grid 121, as components whichcontact the capsule 107 and the contained powdered substance, arefabricated from a material having a low moisture sensitivity, here aplastics material, such as to reduce any tendency to become tacky in thepresence of moisture, and therefore reduce the tendency for the capsule107 and the powdered substance as contained thereby to adhere to thewall of the chamber 105 or the grid 121.

In this embodiment the rupturing mechanism 109 comprises a piercingelement 123, here including two pins, which is operable to pierce thecapsule 107, and thereby provide for the release of the containedpowdered substance on the generation of a flow through the chamber 105.

In one embodiment the capsule 107 is a gelatine capsule.

In another embodiment the capsule 107 can be manufactured from amaterial which has a reduced tendency to become tacky in the presence ofmoisture, as occurs with gelatine capsules, and therefore reduce thetendency for the capsule 107 to adhere to the wall of the chamber 105 orthe grid 121.

In one embodiment the capsule 107 is formed of a cellulose derivative,such as hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose and carboxymethylcellulos.

In another embodiment the capsule 107 can comprise a plastics material,preferably a water insoluble material, such as a polycarbonate.

In one embodiment the capsule 107 can be manufactured from a lightweightmaterial, such as thin-wall section polymeric materials, which reducesthe energy required to move the capsule 107, typically by one or both ofvibration and rotation, and thereby allows the delivery device to beoperated at reduced flow rates, which is particularly advantageous fornasal delivery.

In one embodiment the capsule 107 has a wall section of less than about0.25 mm, and more preferably less than about 0.2 mm.

In an alternative embodiment the capsule 107 can include an outercoating of a material which has a reduced tendency to become tacky inthe presence of moisture, as occurs with gelatine capsules, andtherefore reduce the tendency for the capsule 107 to adhere to the wallof the chamber 105 or the grid 121.

In one embodiment the coated capsule 107 can be formed of gelatine.

In one embodiment the coating can comprise one of parylene,hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylalcohol, acrylic acid polymer, methacrylic acid polymer, ethyl acrylicacid polymer, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxyl methylcelluloseacetate succinate, or any combination of layers thereof.

The delivery device of this embodiment is operative to discharge thepowdered substance from the capsule 107 by rotation and vibration of thecapsule 107, and thus the capsule 107 is preferably formed of a materialor coated with a material which exhibits substantially no tackiness inthe presence of a moist environment, here a saturated exhaled air flow,that is, does not exhibit an increased moisture content at the outersurface thereof, which would prevent reliable rotation and vibration ofthe capsule 107.

In this embodiment the capsule 107 is cylindrical in shape, withhemispherical ends.

In other embodiments the capsule 107 could have other geometric forms,such as spherical, which allows for efficient powder release at low flowrates.

In one embodiment the capsule 107 can comprise two or more parts.

In one alternative embodiment the capsule 107 can be constructed to actas the primary environmental barrier for the powdered substance. Forexample, the capsule 107 could be constructed from a relativelythick-walled cylindrical section of a polymeric material which includestwo metalized thin film closure members which act to seal the ends ofthe cylindrical section and thus enclose the same.

The Venturi unit 110 comprises a first, driving air flow inlet 133 whichis in fluid communication with the mouthpiece unit 111 and provides aconstriction which acts to accelerate the exhaled air flow to deliver adriving air flow at a higher velocity, a second, substance air flowinlet 135 which is in fluid communication with the outlet 119 of thesubstance supply unit 103 and through which, by the reduced localpressure as developed thereat by the Venturi effect, is drawn asubstance air flow from the chamber 105 of the substance supply unit 103which entrains the powdered substance, and an air flow outlet 139 whichis in fluid communication with the nosepiece unit 114 and through whichthe driving air flow and the substance air flow are delivered. In thisembodiment the driving air flow is directed substantiallyperpendicularly to the substance air flow.

This configuration, which utilizes ambient air to entrain the powderedsubstance from the capsule 107, is particularly advantageous, inavoiding the use of exhaled air to entrain the powdered substance.Exhaled air has a high humidity which would lead to condensation both inthe chamber 105 and the capsule 107, which can cause problems in thecomplete entrainment of the powdered substance, both in terms ofadhesion of the capsule 107 to the wall of the chamber 105 and adhesionof the powdered substance to the wall of the capsule 107, particularlywhere the powdered substance is a hygroscopic powder.

The mouthpiece unit 111 comprises a mouthpiece 145, in this embodimentas defined by a tubular section, which is gripped in the mouth of thesubject.

The nosepiece unit 114 comprises a nosepiece 147, in this embodiment asdefined by a tubular section, which is inserted into a nostril of thesubject, in this embodiment to provide a sealing fit therewith.

In this embodiment the nosepiece 147, as a component which contacts thepowdered substance, is fabricated from a material having a low moisturesensitivity, here a plastics material, such as to reduce any tendency tobecome tacky in the presence of moisture, and therefore reduce thetendency for the powdered substance to adhere to the wall of thenosepiece 147.

In one embodiment, where the delivery device is a re-usable device, thechamber 105, which contains the capsule 107, and the nosepiece 147comprise a unitary, replaceable component.

In operation, as illustrated in FIG. 7, a subject operates the rupturingmechanism 109 to rupture the capsule 107, inserts the nosepiece 147 intoone of his/her nostrils, grips the mouthpiece 145 in his/her mouth, andexhales through the mouthpiece 145.

The exhaled air flow is forced through the driving air flow inlet 133 ofthe Venturi unit 110, which acts to deliver the exhaled air flow as adriving air flow over the substance air flow inlet 135 of the Venturiunit 110 and draw a substance air flow, which entrains powderedsubstance, from the chamber 105 of the substance supply unit 103. Thesubstance air flow acts to move the capsule 107, in this embodiment byvibration and rotation, and entrain the powdered substance as containedby the capsule 107.

The exhaled air flow, as then entraining the powdered substance, passesthrough the air flow outlet 139 of the Venturi unit 110, and isdelivered though the nosepiece 147 into one nasal cavity of the subject.

In this embodiment the exhaled air flow has such a pressure as to passaround the posterior margin of the nasal septum, and into the othernasal cavity, thereby achieving a bi-directional air flow as describedin the applicants' earlier WO-A-00/051672.

In one modification of the above-described delivery device, asillustrated in FIGS. 8 and 9, the substance supply unit 103 can beadditionally fluidly connected to the mouthpiece unit 111, in thisembodiment by a flow channel 151 which fluidly connects the mouthpiece145 to the inlet 117 of the substance supply unit 103, such as toprovide for a supplemental air flow to the chamber 105, which assists inentraining the powdered substance as contained by the capsule 107.

By regulating this supplementary air flow and blending the same with theambient air as entrained through the inlet 117 of the substance supplyunit 103, the resulting air flow still has a reduced absolute humidity(water vapour content) as compared with an exhaled air flow, where theambient air is not saturated.

Operation of this device, which is illustrated in FIG. 9, is the same asfor the delivery device of the above-described second embodiment.

FIGS. 10 and 11 illustrate a nasal delivery device in accordance with athird embodiment of the present invention.

The delivery device comprises a substance supply unit 203 which includesa chamber 205 which receives a capsule 207, which contains a meteredamount of a powdered substance which is to be delivered by the deliverydevice, a rupturing mechanism 209 for rupturing the capsule 207, aVenturi unit 210 which is operative to draw an air flow of the ambientatmosphere through the chamber 205, a mouthpiece unit 211 which is influid communication with the Venturi unit 210 and is gripped in use inthe mouth of a subject, and a nosepiece unit 214 which is in fluidcommunication with the Venturi unit 210 and is fitted to one nostril ofthe subject. For ease of illustration, the delivery device isillustrated in an orthogonal configuration, but, in its practicalembodiment, the mouthpiece unit 211 and the nosepiece unit 214 areconfigured for fitting to the mouth and one nostril of the subject.

The substance supply unit 203 includes an inlet 217 which fluidlyconnects the chamber 205 thereof with the ambient atmosphere and anoutlet 219 which fluidly connects the chamber 205 thereof with theVenturi unit 210.

In this embodiment the substance supply unit 203 includes a grid 221,here a gauze, which is disposed at the outlet 219 thereof and acts toprevent the capsule 207 or parts thereof from escaping from the chamber205.

In this embodiment the chamber 205 is cylindrical in shape.

In another embodiment the chamber 205 could be spherical in shape, whichis particularly advantageous in allowing for the release of the powderedsubstance from the capsule 207 when in any operative position.

In this embodiment the chamber 205 and the grid 221, as components whichcontact the capsule 207 and the contained powdered substance, arefabricated from a material having a low moisture sensitivity, here aplastics material, such as to reduce any tendency to become tacky in thepresence of moisture, and therefore reduce the tendency for the capsule207 and the powdered substance as contained thereby to adhere to thewall of the chamber 205 or the grid 221.

In this embodiment the rupturing mechanism 209 comprises a piercingelement 223, here including two pins, which is operable to pierce thecapsule 207, and thereby provide for the release of the containedpowdered substance on the generation of a flow through the chamber 205.

In one embodiment the capsule 207 is a gelatine capsule.

In another embodiment the capsule 207 can be manufactured from amaterial which has a reduced tendency to become tacky in the presence ofmoisture, as occurs with gelatine capsules, and therefore reduce thetendency for the capsule 207 to adhere to the wall of the chamber 205 orthe grid 221.

In one embodiment the capsule 207 is formed of a cellulose derivative,such as hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose and carboxymethylcellulose.

In another embodiment the capsule 207 can comprise a plastics material,preferably a water insoluble material, such as a polycarbonate.

In one embodiment the capsule 207 can be manufactured from a lightweightmaterial, such as thin-wall section polymeric materials, which reducesthe energy required to move the capsule 207, typically by one or both ofvibration and rotation, and thereby allows the delivery device to beoperated at reduced flow rates, which is particularly advantageous fornasal delivery.

In one embodiment the capsule 207 has a wall section of less than about0.25 mm, and more preferably less than about 0.2 mm.

In an alternative embodiment the capsule 207 can include an outercoating of a material which has a reduced tendency to become tacky inthe presence of moisture, as occurs with gelatine capsules, andtherefore reduce the tendency for the capsule 207 to adhere to the wallof the chamber 205 or the grid 221.

In one embodiment the coated capsule 207 can be formed of gelatine.

In one embodiment the coating can comprise one of parylene,hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylalcohol, acrylic acid polymer, methacrylic acid polymer, ethyl acrylicacid polymer, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxyl methylcelluloseacetate succinate, or any combination of layers thereof.

The delivery device of this embodiment is operative to discharge thepowdered substance from the capsule 207 by rotation and vibration of thecapsule 207, and thus the capsule 207 is preferably formed of a materialor coated with a material which exhibits substantially no tackiness inthe presence of a moist environment, here a saturated exhaled air flow,that is, does not exhibit an increased moisture content at the outersurface thereof, which would prevent reliable rotation and vibration ofthe capsule 207.

In this embodiment the capsule 207 is cylindrical in shape, withhemispherical ends.

In other embodiments the capsule 207 could have other geometric forms,such as spherical, which allows for efficient powder release at low flowrates.

In one embodiment the capsule 207 can comprise two or more parts.

In one alternative embodiment the capsule 207 can be constructed to actas the primary environmental barrier for the powdered substance. Forinstance, the capsule 207 could be constructed from a relativelythick-walled cylindrical section of a polymeric material which includestwo metalized thin film closure members which act to seal the ends ofthe cylindrical section and thus enclose the same.

The Venturi unit 210 comprises at least one driving air flow inlet 233which is in fluid communication with the mouthpiece unit 211 andprovides a constriction which acts to accelerate the exhaled air flow todeliver at least one driving air flow at a higher velocity, a second,substance air flow inlet 235 which is fluid communication with theoutlet 219 of the substance supply unit 203 and through which, by thereduced local pressure as developed thereat by the Venturi effect, isdrawn a substance air flow from the chamber 205 of the substance supplyunit 203 which entrains the powdered substance, and an air flow outlet239 which is in fluid communication with the nosepiece unit 214 andthrough which the driving air flow and the substance air flow aredelivered. In this embodiment the at least one driving air flow isdirected substantially parallel to the substance air flow.

In this embodiment the Venturi unit 210 comprises a plurality of airflow inlets 233 which are disposed in an annular arrangement, hereconcentrically, about the substance air flow inlet 235.

This configuration, which utilizes ambient air to entrain the powderedsubstance from the capsule 207, is particularly advantageous, inavoiding the use of exhaled air to entrain the powdered substance.Exhaled air has a high humidity which would lead to condensation both inthe chamber 205 and the capsule 207, which can cause problems in thecomplete entrainment of the powdered substance, both in terms ofadhesion of the capsule 207 and the contained powdered substance to thewall of the chamber 205 and adhesion of the powdered substance to thecapsule 207, particularly where the powdered substance is a hygroscopicpowder.

The mouthpiece unit 211 comprises a mouthpiece 245, in this embodimentas defined by a tubular section, which is gripped in the mouth of thesubject.

The nosepiece unit 214 comprises a nosepiece 247, in this embodiment asdefined by a tubular section, which is inserted into a nostril of thesubject, in this embodiment to provide a sealing fit therewith.

In this embodiment the nosepiece 247, as a component which contacts thepowdered substance, is fabricated from a material having a low moisturesensitivity, here a plastics material, such as to reduce any tendency tobecome tacky in the presence of moisture, and therefore reduce thetendency for the powdered substance to adhere to the wall of thenosepiece 247.

In one embodiment, where the delivery device is a re-usable device, thechamber 205, which contains the capsule 207, and the nosepiece 247comprise a unitary, replaceable component.

In operation, as illustrated in FIG. 11, a subject operates therupturing mechanism 209 to rupture the capsule 207, inserts thenosepiece 247 into one of his/her nostrils, grips the mouthpiece 245 inhis/her mouth, and exhales through the mouthpiece 245.

The exhaled air flow is forced through the at least one driving air flowinlet 233 of the Venturi unit 210, which acts to deliver the exhaled airflow as a driving air flow past the substance air flow inlet 235 of theVenturi unit 210 and draw a substance air flow, which entrains powderedsubstance, from the chamber 205 of the substance supply unit 203. Thesubstance air flow acts to move the capsule 207, in this embodiment byvibration and rotation, and entrain the powdered substance as containedby the capsule 207.

The exhaled air flow, as then entraining the powdered substance, passesthrough the air flow outlet 239 of the Venturi unit 210, and isdelivered though the nosepiece 247 into one nasal cavity of the subject.

In this embodiment the exhaled air flow has such a pressure as to passaround the posterior margin of the nasal septum, and into the othernasal cavity, thereby achieving a bi-directional air flow as describedin the applicants' earlier WO-A-00/051672.

FIGS. 12 to 14 illustrate a nasal delivery device in accordance with afourth embodiment of the present invention.

The delivery device comprises a substance supply unit 303 which includesa chamber 305 which receives a capsule 307, which contains a meteredamount of a powdered substance which is to be delivered by the deliverydevice, a rupturing mechanism 309 for rupturing the capsule 307, a gassupply unit 310 which is operative to deliver a gas flow through thechamber 305, a mouthpiece unit 311 which is in fluid communication withthe chamber 305 and is gripped in use in the mouth of a subject, and anosepiece unit 314 which is in fluid communication with the chamber 305and is fitted to one nostril of the subject. For ease of illustration,the delivery device is illustrated in an elongate configuration, but, inits practical embodiment, the mouthpiece unit 311 and the nosepiece unit314 are configured for fitting to the mouth and one nostril of thesubject.

The substance supply unit 303 includes an inlet 317 which fluidlyconnects the chamber 305 thereof with the gas supply unit 310 and anoutlet 319 which fluidly connects the chamber 305 thereof with themouthpiece unit 311 and the nosepiece unit 314.

In this embodiment the substance supply unit 303 includes a grid 321,here a gauze, which is disposed at the outlet 319 thereof and acts toprevent the capsule 307 or parts thereof from escaping from the chamber305.

In this embodiment the chamber 305 is cylindrical in shape.

In another embodiment the chamber 305 could be spherical in shape, whichis particularly advantageous in allowing for the release of the powderedsubstance from the capsule 307 when in any operative position.

In this embodiment the chamber 305 and the grid 321, as components whichcontact the capsule 307 and the contained powdered substance, arefabricated from a material having a low moisture sensitivity, here aplastics material, such as to reduce any tendency to become tacky in thepresence of moisture, and therefore reduce the tendency for the capsule307 and the powdered substance as contained thereby to adhere to thewall of the chamber 305 or the grid 321.

In this embodiment the rupturing mechanism 309 comprises a piercingelement 323, here including two pins, which is operable to pierce thecapsule 307, and thereby provide for the release of the containedpowdered substance on the generation of a flow through the chamber 305.

In one embodiment the capsule 307 is a gelatine capsule.

In another embodiment the capsule 307 can be manufactured from amaterial which has a reduced tendency to become tacky in the presence ofmoisture, as occurs with gelatine capsules, and therefore reduce thetendency for the capsule 307 to adhere to the wall of the chamber 305 orthe grid 321.

In one embodiment the capsule 307 is formed of a cellulose derivative,such as hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose and carboxymethylcellulose.

In another embodiment the capsule 307 can comprise a plastics material,preferably a water insoluble material, such as a polycarbonate.

In one embodiment the capsule 307 can be manufactured from a lightweightmaterial, such as thin-wall section polymeric materials, which reducesthe energy required to move the capsule 307, typically by one or both ofvibration and rotation, and thereby allows the delivery device to beoperated at reduced flow rates, which is particularly advantageous fornasal delivery.

In one embodiment the capsule 307 has a wall section of less than about0.25 mm, and more preferably less than about 0.2 mm.

In an alternative embodiment the capsule 307 can include an outercoating of a material which has a reduced tendency to become tacky inthe presence of moisture, as occurs with gelatine capsules, andtherefore reduce the tendency for the capsule 307 to adhere to the wallof the chamber 305 or the grid 321.

In one embodiment the coated capsule 307 can be formed of gelatine.

In one embodiment the coating can comprise one of parylene,hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylalcohol, acrylic acid polymer, methacrylic acid polymer, ethyl acrylicacid polymer, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxyl methylcelluloseacetate succinate, or any combination of layers thereof.

The delivery device of this embodiment is operative to discharge thepowdered substance from the capsule 307 by rotation and vibration of thecapsule 307, and thus the capsule 307 is preferably formed of a materialor coated with a material which exhibits substantially no tackiness inthe presence of a moist environment, here a saturated exhaled air flow,that is, does not exhibit an increased moisture content at the outersurface thereof, which would prevent reliable rotation and vibration ofthe capsule 307.

In this embodiment the capsule 307 is cylindrical in shape, withhemispherical ends.

In other embodiments the capsule 307 could have other geometric forms,such as spherical, which allows for efficient powder release at low flowrates.

In one embodiment the capsule 307 can comprise two or more parts.

In one alternative embodiment the capsule 307 can be constructed to actas the primary environmental barrier for the powdered substance. Forinstance, the capsule 307 could be constructed from a relativelythick-walled cylindrical section of a polymeric material which includestwo metalized thin film closure members which act to seal the ends ofthe cylindrical section and thus enclose the same.

In this embodiment the gas supply unit 310 comprises a high-pressurereservoir 341, preferably at a pressure of from about 1 bar to about 10bar, and more preferably at a pressure from about 2 bar to about 10 bar,which, when actuated, delivers a gas flow which acts to drive powderrelease from the capsule 307. In one embodiment the reservoir 341 can bea pre-filled volume of gas at high-pressure, such as a pressurizedcanister which contains a propellant. In an alternative embodiment thereservoir 341 can be charged using a pump mechanism.

In this embodiment the gas supply unit 310 is configured such as to beactuated on the generation of a predetermined flow rate through themouthpiece unit 311, typically a flow rate of from about 10 l/min toabout 50 l/min.

In another embodiment the gas supply unit 310 can be configured such asto be actuated on the generation of a predetermined pressure at themouthpiece unit 311.

In a further embodiment the gas supply unit 310 can be configured suchas to be manually actuated.

This configuration is particularly advantageous, in avoiding the use ofexhaled air to entrain the powdered substance, and in one embodimentallowing the use of a dry gas. Exhaled air has a high humidity whichwould lead to condensation both in the chamber 305 and the capsule 307,which can cause problems in the complete entrainment of the powderedsubstance, both in terms of adhesion of the capsule 307 and thecontained powdered substance to the wall of the chamber 305 and adhesionof the powdered substance to the capsule 307, particularly where thepowdered substance is a hygroscopic powder.

The mouthpiece unit 311 comprises a mouthpiece 345, in this embodimentas defined by a tubular section, which is gripped in the mouth of thesubject.

The nosepiece unit 314 comprises a nosepiece 347, in this embodiment asdefined by a tubular section, which is inserted into a nostril of thesubject, in this embodiment to provide a sealing fit therewith.

In this embodiment the nosepiece 347, as a component which contacts thepowdered substance, is fabricated from a material having a low moisturesensitivity, here a plastics material, such as to reduce any tendency tobecome tacky in the presence of moisture, and therefore reduce thetendency for the powdered substance to adhere to the wall of thenosepiece 347.

In one embodiment, where the delivery device is a re-usable device, thechamber 305, which contains the capsule 307, and the nosepiece 347comprise a unitary, replaceable component.

Operation of the delivery device will now be described hereinbelow withreference to FIGS. 13 and 14 of the accompanying drawings.

As illustrated in FIG. 13, a subject operates the rupturing mechanism309 to rupture the capsule 307, inserts the nosepiece 347 into one ofhis/her nostrils, grips the mouthpiece 345 in his/her mouth, and exhalesthrough the mouthpiece 345.

The exhaled air flow is delivered though the nosepiece 347 into onenasal cavity of the subject.

In this embodiment, as illustrated in FIG. 14, when the exhaled air flowhas a predetermined flow rate, the gas supply unit 310 is actuated, suchas to deliver a gas flow through the chamber 305. This gas flow acts tomove the capsule 307, in this embodiment by vibration and rotation, andentrain the powdered substance as contained by the capsule 307, and thegas flow, as then entraining the powdered substance, is delivered intothe exhaled air flow passing through the nosepiece 347 into one nasalcavity of the subject, such that the exhaled air flow entrains thepowdered substance into the nasal cavity of the subject. Thisconfiguration is particularly advantageous where the gas supply unit 310is a pressurized canister, as the gas flow from a pressurized canisteris cold, and this cold gas is mixed with the warmer exhaled air flowprior to delivery to the nasal cavity.

In this embodiment the exhaled air flow has such a pressure as to passaround the posterior margin of the nasal septum, and into the othernasal cavity, thereby achieving a bi-directional air flow as describedin the applicants' earlier WO-A-00/051672.

In one modification, as illustrated in FIG. 15, the gas supply unit 310could comprise a charged turbine 353, for example, a propeller which ischarged by a resilient element, such as spring. With this configuration,on actuation of the gas supply unit 310, stored energy drives theturbine to entrain atmospheric air through the chamber 305 whichcontains the capsule 307.

Finally, it will be understood that the present invention has beendescribed in its preferred embodiments and can be modified in manydifferent ways without departing from the scope of the invention asdefined by the appended claims.

In one embodiment the powdered substance can also be formulated, forexample, by coating or blending, such as to reduce the hygroscopicityand transiently increase the dissolution time, and thus reduce any lossof powdered substance in the device due to interaction with condensationon the internal surfaces of the device.

Also, the delivery devices of the described embodiments have beendescribed in relation to the use of capsules 7, 107, 207, 307. It is tobe understood that the present invention has application with any kindof powder delivery system, including blisters and metering from bulk,and can be configured as a single-use or multi-use device.

Furthermore, the delivery device of the first-described embodiment couldbe modified to incorporate a thermoelectric device as the heat exchanger27, for example, a device which utilizes the Peltier effect, asillustrated in FIG. 16.

In another modification, as illustrated in FIG. 17, the delivery deviceof the first-described embodiment could be modified such that thechamber 5 is substantially spherical in shape, which is particularlyadvantageous in allowing for the release of the powdered substance fromthe capsule 7 in any operative position, and the capsule 7 could bespherical.

1. (canceled)
 2. A nasal delivery device for delivering a substance to anasal cavity of a subject comprising: a substance supply unit includingan inlet and an outlet, the substance supply unit configured to receivea substance container holding the substance; a mouthpiece unit includinga mouthpiece in fluid communication with the inlet of the substancesupply unit, and a plurality of flow channels disposed between themouthpiece and the inlet of the substance supply unit.
 3. The deliverydevice of claim 2, wherein the plurality of flow channels extends only aportion of the distance from the mouthpiece to the inlet of thesubstance supply unit.
 4. The delivery device of claim 2, furthercomprising a flow path from the mouthpiece to the substance supply unit,the flow path including a constriction adjacent to the inlet of thesubstance supply unit.
 5. The delivery device of claim 2, wherein theplurality of flow channels are arranged in a zig-zag configuration. 6.The delivery device of claim 2, wherein the plurality of flow channelsare arranged in a serpentine configuration.
 7. The delivery device ofclaim 2, wherein each of the plurality of flow channels includes asubstantially circular cross section.
 8. The delivery device of claim 2,wherein each of the plurality of flow channels includes a substantiallyrectangular cross section.
 9. The delivery device of claim 2, furtheringcomprising a rupturing mechanism, the rupturing mechanism including apiercing element for rupturing the substance container.
 10. The deliverydevice of claim 2, wherein the substance is a powder.
 11. The deliverydevice of claim 2, wherein the substance container is a capsule.
 12. Thedelivery device of claim 2, further comprising a filter disposedadjacent the outlet of the substance supply unit.
 13. The deliverydevice of claim 12, wherein the filter is disposed between the substancesupply unit and the nosepiece.
 14. A nasal delivery device fordelivering a substance to a nasal cavity of a subject comprising: asubstance supply unit including an inlet and an outlet, the substancesupply unit configured to receive a substance container holding thesubstance; a mouthpiece unit including a mouthpiece in fluidcommunication with the inlet of the substance supply unit; a pluralityof flow channels disposed between the mouthpiece and the inlet of thesubstance supply unit; and a nosepiece unit including a nosepiece forfitting to a nasal cavity of the subject, the nosepiece in fluidcommunication with the outlet of the substance supply unit.
 15. Thedelivery device of claim 14, wherein the plurality of flow channelsextends only a portion of the distance from the mouthpiece to the inletof the substance supply unit.
 16. The delivery device of claim 14,further comprising a flow path from the mouthpiece to the substancesupply unit, the flow path including a constriction adjacent to theinlet of the substance supply unit.
 17. The delivery device of claim 14,wherein the plurality of flow channels are arranged in a zig-zagconfiguration.
 18. The delivery device of claim 14, wherein theplurality of flow channels are arranged in a serpentine configuration.19. The delivery device of claim 14, wherein each of the plurality offlow channels includes a substantially circular cross section.
 20. Thedelivery device of claim 14, wherein each of the plurality of flowchannels includes a substantially rectangular cross section.
 21. Thedelivery device of claim 14, further comprising a rupturing mechanismcomprising a piercing element for rupturing the substance container. 22.The delivery device of claim 14, wherein the substance is a powder. 23.The delivery device of claim 14, wherein the substance container is acapsule.
 24. The delivery device of claim 14, further comprising afilter disposed adjacent the outlet of the substance supply unit. 25.The delivery device of claim 24, wherein the filter is disposed betweenthe substance supply unit and the nosepiece.
 26. A nasal delivery devicefor delivering a substance to a nasal cavity of a subject, comprising: asubstance supply unit including an inlet, an outlet, a container chamberdisposed between the inlet and the outlet, and a rupturing mechanism,the container chamber configured to contain a substance container, andthe rupturing mechanism including a piercing element configured torupture the substance container; a mouthpiece unit including amouthpiece in fluid communication with the inlet of the substance supplyunit; a plurality of flow channels disposed between the mouthpiece andthe inlet of the substance supply unit, the plurality of flow channelsbeing arranged in a serpentine configuration; and a nosepiece unitincluding a nosepiece for fitting to a nasal cavity of the subject and afilter, the nosepiece in fluid communication with the outlet of thesubstance supply unit and the filter disposed at the outlet of thesubstance supply unit; a constriction disposed in a flow path betweenthe mouthpiece and the substance supply unit; and a substance containercomprising a capsule containing a powdered substance.
 27. In combinationa substance supply unit and a plurality of unitary components which arereplaceably fitted to the substance supply unit with each operation ofthe substance supply unit to provide a delivery device for delivery of asubstance to a nasal cavity of a subject, wherein: the substance supplyunit includes a mouthpiece through which the subject in use exhales soas to entrain the substance from the substance supply unit; and theunitary components each comprise a container chamber which contains asubstance-containing container and is in fluid communication with themouthpiece, and a nosepiece which is in fluid communication with thecontainer chamber.